Abstract
Tuberculosis (TB) is an infectious airborne disease that is caused by Mycobacterium tuberculosis (Mtb). The World Health Organization (WHO) reported that TB was responsible for 1.4 million deaths worldwide in 2019. Most of these deaths occurred in poor African and Asian countries. Furthermore, 10 million TB-related cases were reported globally in the same year. Currently, drug susceptible TB is treated over a period of 6 to 9 months using a concoction of 4 first line drugs namely, Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. One of the challenges associated with TB treatment is the development of drug resistant TB known as multidrug-resistant TB (MDR-TB) and extensively drug-resistant (XDR-TB). These drug resistant TB strains are more difficult to treat and can result in mortality of the patient. One of the ways to overcome drug resistance is through the development of new drug candidates with new modes of action. In this study we focused on the optimization of 6-dialkylaminopyrimidine carboxamides as potential anti-TB agents. A series of dialkylaminopyrimidine carboxamides has been reported to show good anti-TB activities with a probable novel mode of action (MOA) and relatively low cytotoxicity. The novel MOA that is not shared with any of the known TB drugs, although there is inconclusive data for target site identification, is enough to provoke some interest in these series. However, the lipophilic nature of these compounds reduces their kinetic solubility in aqueous media which affects their bioavailability. A hit compound (44) was identified in a phenotypic whole-cell high throughput screening of a SoftFocus library. Wilson and co-workers optimized the lead compound by synthesizing its derivatives and used these to establish the functional groups essential for activity through structure activity relationship studies. The most active compound (48) from the synthesized series also showed poor kinetic solubility (Figure 1a).
M.Sc. (Chemistry)